Oxime esters of 19-norandrostenes



3,437,674 OXIME ESTERS F 19-NORANDROSTENES Arvin P. Shrotf, Piscataway,N.J., assignor to Ortho Pharmaceutical Corporation, a corporation of NewJersey No Drawing. Filed July 6, 1966, Ser. No. 563,081 lint. Cl. C07c169/12 US. Cl. 260397.1 7 Claims ABSTRACT OF THE DISCLOSURE 3-oximeesters of 19-norandrostenes which are potent oral antilittering agents.

This invention relates to novel steroids. More particularly, theinvention relates to 3-oxime esters of 19- norandrostenes.

The compounds of the invention have the general OCOR wherein R is alkylof from 1 to carbon atoms, R' is alkyl of from 1 to 10 carbon atoms, andR" is alkyl of from 1 to 10 carbon atoms.

The compounds of the invention are potent oral antilittering agents atdose levels between 0.25 mg./kg. body weight to 1.0 lug/kg. body Weight.At these dose levels, the compounds of the invention do not possess anyappreciable progestational or antiovulatory activity.

The 3-oxime esters of the invention are prepared from the oximes ofnorethindrone esters, the preparations of which are described in mycopending application S.N. 502,384 filed Oct. 22, 1965 now abandoned.

The compounds of the invention are prepared by esterifying oximes ofdiiferent norethindrone esters with an appropriate acid anhydride, suchas acetic anhydride, propionoic anhydride, n-valeric anhydride, caprylicanhydride, etc., or by treating different norethindrone esters with acarboxyalkyloxyamine.

States Patent 0 The following examples are illustrative of the preparation of the compounds of the invention.

EXAMPLE I N,17B-diacetoxy-17a-ethynyl-19-norandrost-4- en-3-one oxime Asolution containing 3.0 g. of 17a-ethynyl-17B-acetoxy-19-norandrost-4-en-3-one oxime in 5.0 ml. of pyridine is treated with9.0 ml. of acetic anhydride and stirred at room temperature for 15minutes. The mixture is poured into a large amount of ice and water andneutralized with ammonium hydroxide. The solid portion is collected byfiltration, dried and recrystallized from hexane to give N,17,Bdiaceto-xy 17a-ethynyl-l9-norandrost-4-en-3-one oxime. M.P. 142144 C.

max.

243 III/L Calcd. for C H NO C, 72.51; H, 7.86; N, 3.52. Found: C, 72,54;H, 8.01; 'N, 3.73.

EXAMPLE IIN-iso-butyroxy-17,8-acetoxy-17a-ethynyll9-norandrost-4-en-3-one oximeCalcd. for C H NO C, 73.38; H, 8.29; N, 3.29. Found: C, 73.31; H, 8.31;N, 3.53.

EXAMPLE III N-propionoxy-17B-acetoxy-17ot-ethynyl-19-norandrost-4-en-3-one oxime Following the procedure of Example I or II,but using propionoic anhydride as the esterifying agent, N-propionoxy17,6 acetoxy-lh-ethynyl-l9-norandrost-4-en-3-one oxime is recrystallizedfrom hexane. M.P. 152154 C.

max.

Calcd. for C H NO C, 72.96; Found: C, 72.69; H, 8.24; N, 3.49.

EXAMPLE IV N-caproxy-17B-acetoxy-17a-ethynyl-19-norandrost- 4-en-3-oneoxime Following the procedure of Example I or II, but using caproicanhydride as the esterifying agent, =N-caproxy-17fl-acetoxy-17m-ethynyl-19-norandrost-4-en-3-one oxime isrecrystallized from hexane. M.P. 102-104" C.

Calcd. for C H NO C, 74.14; Found: C, 74.03; H, 8.55; N, 3.33.

EXAMPLE V 3-(O-carboxymethyl)-17B-acetoxy-17a-ethynyl-19-norandrost-4-en-3-0ne oximel7a-ethynyl-17,8-acetoxy-19-norandrost-4-en-3-one (2.0

g.) is dissolved in 10 ml. of pyridine and treated with 1.0 g. ofcarboxymethoxylamine hemi hydrochloride. The mixture is heated on asteam bath for 0.5 hour and poured into a large amount of ice and water.The solid material is collected by filtration and recrystallized frommethanol- Water to give 3 (O-carboxymethyl) l7/3-acetoxy-17aethynyl 19norandrost 4 en-3-one oxime. MP. 23 6- 237 C.

A222? 248 mu Calcd. for C H NO C, 69.71; H, 7.56; N, 3.39.

Found: C, 69.48; H, 7.60; N, 3.37. Similarly there may be prepared:

EXAMPLE VI N,17fl-diacetoxy-17u-ethyny1-19-norandrost-4,6-dien-3- oneoxime Calcd. for C H NO C, 72.88; H, 7.39; N, 3.54. Found: C, 73.13; H,7.58; N, 3.79.

EXAMPLE VII N-propionoxy-17fl-acetoxy-l7a-ethynyl-19-norandrost-4,6-dien-3-one oxime Following the procedure of Example VI but usingpropionic anhydride as the esterifying agent, N-propionoxy 17 6acetoxy-17a-ethynyl-19-norandrost-4,6-dien-3- one oxime isrecrystallized from ethyl acetate-hexane. M.P. 213-214 C.

Calcd. for C H NO C, 73.32; H, 7.63; N, 3.42. Found: C, 73.36; H, 7.77;N, 3.55.

Similarly there may be prepared:N-caproxy-17B-acetoxy-17a-ethynyl-l9-norandrost-4,6-

dien-3-one oxime,

N-isobutyroxy-17 3-acetoxy-17a-ethynyl-19-norandrost- 4,6-dien-3-oneoxime,

4 3-(O-carboxymethyl)-17fiacetoxy-17ot-ethynyl-19-norandrost-4,6-dien-3-one oxime,N,17,8-dicaproxy-17u-ethynyl-19-r1orandrost-4,6-dien-3- one oxime,N-acetoxy-17B-caproxy-17u-ethynyl-19-norandrost-4,6-

dien-3-one oxime, N-isobutyroxy-l7,3caproxy-17u-ethynyl-19-norandrost-4,6-dien-3-one oxime,N-acetoxy-l713-enanthoxy-17a-ethyny1-19-norandrost-4,6-

dien-3-one oxime, N-isobutyroxy-l7B-enanthoxy-17a-ethynyl-l9-norandrost-4,6-dien-3-one oxime,N-acetoxy-UB-decanoxy-17a-ethynyl-19-norandrost-4,6-

dien-3-one oxime,

g N-propionoxy-17B-decanoxy-17u-ethynyl-19-norandrost- 4,6-dien-3-oneoxime.

What is claimed is: 1. A compound selected from the group consisting of:

o 0 OR (\I 415011 1? HO CRON:

and

o o o R wherein R is selected from the group consisting of alkyl of from1 to 10 carbon atoms, R is methylene, and R" is selected from the groupconsisting of alkyl of from 1 to 10 carbon atoms, and the dotted lineindicates an optional double bond in the 6-7 position.

2. 3 (O-carboxymethyl)-l7fi-acetoxy-17a-ethynyl-19-norandrost-4-en-3-one oxime. according to claim 1.

3. N,17,8 diacetoxy 17u-ethynyl-19-norandrost-4,6- dien-3-one oximeaccording to claim 1.

4. N-propionoxy 17fi-acetoxy-17a-ethynyl-19-norandrost-4,6-dien-3-oneoxime according to claim 1.

5. N-caproxy 17/3-acetoxy-17a-ethynyl-19-norandrost- 4,6-dien-3-oneoxime according to claim 1.

6. N-iso-butyroxy 17,6-acetoxy-17aethynyl-19-norandrost-4,6-dien-3-oneoxime according to claim 1.

7. 3 (O-carboxymethyl)-l7B-acetoxy-17u-ethynyl-19-norandrost-4,6-dien-3-one oxime according to claim 1.

References Cited UNITED STATES PATENTS 3,299,107 1/1967 Mazur 260397.5

LEWIS GOTTS, Primary Examiner.

E. G. LOVE, Assistant Examiner.

U.S. C1. X.R. 260397.5, 999.

